Several lines of evidence support the idea that alpha-synuclein plays a key role in both inherited and sporadic Parkinsons disease. First, mutations in the a-synuclein gene, including multiplication variants, are causative for PD or similar diseases. Second, common genetic variants around the a-synuclein locus alter lifetime risk of sporadic PD. Third, the a-synuclein protein is a major component of Lewy bodies, the characteristic pathological inclusion found in PD. However, understanding why a-synuclein is associated with characteristic patterns of neuronal cell death is unclear. In the current period, we have been involved in two studies trying to understand why a-synuclein might be toxic and how this might be prevented. In the first, we have shown that a-synuclein in its putatively toxic oligomeric form can limit the efficiency of lysosomal clearance of proteins in the cell. This may be related to the observation that a lysosomal enzyme, glucocerebrosidase, is associated genetically associated with risk of PD. In the second, we were able to show that farnesyl transferase inhibitors can limit a-synuclein toxicity in cell culture models. This may be related to inhibition of another protein turnover enzyme, ubiquitin-C terminal hydrolase 1 (UCHL1). However, the fundamental question of how a-synuclein kills neurons is still unclear as a direct molecular target remains to be identified. Therefore, future work will be directed at developing large scale screening methods to address these problems.